tbuckley/cabot-search huggingface dataset:
Molecular characterization of metastatic colorectal cancer (mCRC) in patients (pts) treated with cetuximab and pembrolizumab.
Authors: Christos Fountzilas, Spencer Rosario, Henry G. Withers, Sarbajit Mukherjee, David L Bajor, Joel N. Saltzman, Chong Wang, Kristopher Attwood, Erik S. Knudsen, Agnieszka K Witkiewicz, Renuka V. Iyer, Patrick M Boland
Journal: Journal of Clinical Oncology (2023)

178 Background: Anti-EGFR therapy has the potential to increase a localized anti-tumor immune response. We recently published the results of a phase Ib/II trial of the anti-EGFR antibody cetuximab in combination with the anti-PD1 antibody pembrolizumab in pts with advanced, RASwt CRC (PMID: 34645646). Despite its partial local immunologic efficacy, this combination of cetuximab and pembrolizumab was inactive. Here we present the results of comprehensive molecular characterization of pts with tumors amenable to DNA and RNA sequencing. Methods: Forty-two pts with RASwt mCRC were treated with cetuximab plus pembrolizumab. Archival or fresh tumor samples were obtained at baseline and, in select patients, on-treatment. Tumor samples underwent targeted DNA sequencing and whole transcriptome sequencing. Gene set enrichment analysis (GSEA), metabolic dysregulation assessment, and immune deconvolution were performed. Genomic data were linked to clinical outcomes. Results: Eighteen pts had tissue available for dual DNA/RNA extraction and sequencing. Of these, 10 had available matched on-treatment tumor samples. The most common mutations detected in protein coding regions were TP53 (14 pts), ERBB4 (5 pts), CDKN2A and APC (6 pts each). There were no statistically significant differences in progression-free survival (PFS) in pts with and without resistance-associated mutations (i.e., RAS, MET, ERBB4). Further, there was no significant difference associated with the consensus molecular subtype (CMS). However, when we compared patients with stable/increased tumor change percentage to those with decreased tumor change percentage, we found downstream transcriptional differences associated with altered metabolism, and in particular lipid and amino acid metabolism. Conclusions: We identified a significant number of patients with mutations predicting resistance to either or both cetuximab and pembrolizumab; however, none were associated with survival. However, we did identify metabolic pathways of interest, which may be associated with response to therapy. It is important to note, our analysis is limited by the small number of specimens (Trial registration NCT02713373). Clinical trial information: NCT02713373 .
Plasma phosphocreatine (PC) as a predictive biomarker for immune checkpoint inhibition in patients with refractory metastatic colorectal cancer (mCRC): Analysis of the CCTG CO.26 trial.
Authors: Lucy Xiaolu Ma, Jonathan M. Loree, Derek J. Jonker, Hagen Fritz Kennecke, Scott R. Berry, Felix Couture, Chaudhary E. Ahmad, John R. Goffin, Petr Kavan, Mohammed Harb, Bruce Colwell, Setareh Samimi, Benoit Samson, Tahir Abbas, Nathalie Aucoin, Francine Aubin, Sheryl L. Koski, Dongsheng Tu, Christopher J. O'Callaghan, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2023)

183 Background: In response to energetic stress, colorectal cancer cells secrete creatine kinase brain-type (CKB). CKB converts creatine and ATP from the extracellular matrix to PC, which is imported intracellularly to sustain survival and metastatic spread. In addition, PC modulates immune cell functions and may play a role in mediating responses to immune checkpoint inhibition. CO.26 was a phase II trial (NCT02870920) that randomized patients (pts) with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). In an exploratory, post-hoc analysis, we investigated the role of plasma PC as a predictive biomarker for response to D+T. Methods: PC concentrations were determined from pre-treatment blood samples with HPLC-tandem mass spectrometer. A minimum p-value approach was used to select an optimum cut-off value which dichotomized patients into low (&lt; 95.6 ng/ml) versus high (≥ 95.6 ng/ml) groups predictive for benefit. Cox proportional hazard models were used to analyze predictive impacts of PC on progression free survival (PFS) and overall survival (OS). Results: Of 180 pts enrolled, pre-treatment blood samples were available for 162 pts (N =115 for D+T; 47 BSC). Pre-treatment PC was low in 15% (N=24) and high in 85% (N=138). There were no differences in baseline characteristics between pts included in this analysis and the total study pts, or PC low and high pts. D+T improved OS significantly in PC low pts (median OS 4.7 months vs 2.3 months; Hazard Ratio (HR) 0.32, 95% confidence interval (CI): 0.11 – 0.95, p = 0.03). There was no improvement in PC high pts with D+T (median OS 6.8 vs 5.2 months; HR 0.80, 95% CI: 0.55 – 1.17, p = 0.24. Interaction p &lt; 0.0001). Plasma PC values had no impact on PFS and rates of disease control. Conclusions: Pts with low plasma PC derived more benefit from immune checkpoint inhibition with D+T in pts with refractory mCRC. Further prospective validation studies are needed. Predictive analysis for OS with pre-treatment PC levels dichotomized by minimum p approach. [Table: see text]
An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab and bevacizumab therapy in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.
Authors: Tanios S. Bekaii-Saab, Mark Yarchoan, Muneeb Ahmed, David Michael Cohan, Wen Wee Ma
Journal: Journal of Clinical Oncology (2023)

TPS623 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of bevacizumab (Bev) and atezolizumab (Atezo) is the preferred frontline therapy for advanced HCC, but a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment, mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that expresses the fusogenic GALV-GP R- protein, an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the tumor microenvironment is intended to provide systemic anti-tumor activity and reverse therapeutic resistance to anti-PD-1/PD-L1 agents. Pre-clinical data has demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev supporting the clinical combination of RP3 with Bev. RP3 combined with anti-PD1 therapy has demonstrated clinical activity and safety in pts with various malignant solid tumors. This study will evaluate the safety and efficacy of RP3 combined with Atezo and Bev as 1 st (1L) and 2 nd (2L) line systemic therapies for inoperable and advanced HCC. Methods: The 1L and 2L cohorts will each enroll up to 30 pts with advanced, unresectable HCC. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following one prior line of systemic therapy, which must have included a PD-(L)1 directed agent. Key inclusion criteria include advanced unresectable HCC with at least 1 measurable tumor of ≥1 cm in longest diameter, Childs-Pugh Class A, and ECOG Score of 0 or 1. Important exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding, and macroscopic invasion of tumor into major blood vessels and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in 1L cohort will receive 1200 mg Atezo and 15mg/kg Bev Q3W together with RP3 intratumorally (IT) Q3W for a total of up to 8 doses. In 2L pts will receive RP3 Q2W for 4 doses with Bev Q3W starting on C1D1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint includes overall response rate (ORR) by RECIST v1.1. Secondary endpoints are safety, ORR using HCC mRECIST, duration of response, complete response rate, and progression-free survival.
Anlotinib combined with nab-paclitaxel and cisplatin as neoadjuvant treatment (NAT) for esophageal squamous cell carcinoma (ESCC): Update results of a single-arm, phase II clinical trial.
Authors: Yan-Feng Zhang, Xiao-Bing Li, Yong-Gui Hong, Xiao-Ming Li, Wei-Min Liang, Zhi-Xin Zheng, Guang-Yi Yang, Yan-Yan Wen, Heng Cao, Wei-Long Wu, Wen-Zhong Su
Journal: Journal of Clinical Oncology (2023)

366 Background: Neoadjuvant chemoradiation is associated with improved OS, DFS and pCR in patients (pts) with locoregional ESCC. Nevertheless, it is still needed to explore more tolerable preoperative regimen in ESCC. Anlotinib is a multi-targeted angiogenesis inhibitor and has been demonstrated effective and safe as second-line monotherapy in ESCC patients in China (NCT02649361). The combination therapy might be a possible strategy. The preliminary results of nab-paclitaxel and cisplatin combined with anlotinib as NAT for ESCC had been reported in 2022 ASCO (e16015) and 2022 ESMO (1252P). Here, we updated the results. Methods: ESCC pts with clinical stage II-III and radical resectable potential were recruited. The calculated sample size was 62 and eligible pts received anlotinib (12mg, po, d1~14, q3w), nab-paclitaxel (175mg/m 2 , iv, q3w) and cisplatin (20mg/m 2 , iv, d1~3, q3w) for 2 cycles as NAT before surgery. Four weeks later, pts underwent radical surgery after exclusion of contraindications. The primary endpoint was ORR assessed by investigator per RECIST 1.1, secondary endpoints included R0 resection rate, DFS, OS, DCR and safety. Results: From Apr 2021 to Sep 2022, 40 eligible pts were enrolled. Among them, 29 pts underwent surgery after 2 cycles of NAT, 6 pts chose other treatment options, and 5 pts are still receiving NAT. Pts who had received surgery (n=29) were included in this analysis. In best overall response assessment, ORR was 86.2% (95%CI: 68.3-96.1%) and DCR was 100.0% (95%CI: 88.1-100.0%). R0 resection was achieved in all 29 pts who underwent subsequent esophagectomy. Among them, 4 pts (13.8%) were confirmed to be pCR. At the data cut-off date (September 15, 2022), the median DFS was not yet available. Among the 40 enrolled cases, the safety profile revealed that the most common treatment-emergent adverse events (TEAEs) were gastrointestinal reactions (80.0%), liver damage (15.0%), nausea (12.5%), hypokalemia (10.0%) and myelosuppression (10.0%). Grade 3 TEAEs occurred in 2 pts (5.0%) included neutropenia (2.5%) and gastrointestinal reactions (2.5%). Conclusions: Anlotinib in combination with nab-paclitaxel and cisplatin is safe and feasible as neoadjuvant therapy in patients with ESCC.
Long-term outcomes from adding durvalumab to neoadjuvant treatment of operable gastroesophageal cancers: Results from a multicenter study LUD2015-005.
Authors: Mark R. Middleton, Ioannis Karydis, Xin Lu, Aileen Ryan, Ralph Rudolph Venhaus, Kristen Auferio Ramirez, Mary Macri, Toni Ricciardi, Megan Lawrence, Martin Scott-Brown, Gareth Owen Griffiths, Linda Collins, Lucinda Griffiths, Sam Wilding, Simon Lord, Richard Owen, Russell D. Petty
Journal: Journal of Clinical Oncology (2023)

398 Background: Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors to conventional chemotherapy for patients with gastroesophageal cancer (GEC). Large scale studies of chemoimmunotherapy prior to and after surgery are under way. We sought to characterise the effects of the PDL1 inhibitor durvalumab (D) with standard neo-adjuvant chemo(radio)therapy regimens in an open label phase I/II study in patients (pts) with operable GEC (LUD2015-005, NCT02735239, EudraCT 2015-005298-19). Methods: In pts identified as suitable for potentially curative surgery we gave D (750mg q2w) alongside their standard treatment. Pts had D only at first then Oxaliplatin and Capecitabine (CapOx) q3w or fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT) starting with the third cycle of D. Chemotherapy and further D were given for 6 (CapOx) or 8 (FLOT) weeks before pts had surgery and for up to 12 further infusions of D after operation. Patients on FLOT could also have more chemotherapy. Pts suitable for chemoradiotherapy (CXRT, CROSS regimen) were offered two cycles of D before starting their treatment, and were able to have up to 12 further cycles after recovering from surgery. Participants were followed for toxicity, response and survival from the time of study enrolment until death, for 3 years or until June 2022 when the study ended. Results: 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. All were evaluable for safety and efficacy. Treatment side effects were as expected for the agents used with diarrhoea, nausea and fatigue the most commonly reported and no new safety signals. 156 of 160 planned pre-op D doses were given. Only 2 out of 35 patients did not have surgery, both due to progressive disease on D-CXRT. 23 of the 33 patients having surgery had post-operative treatment. Amongst 33 evaluable pts 2 (5.7%) and 6 (17.1%) had complete or partial pre-op responses (RECIST) and 3 (8.6%) progression prior to surgery. Tumor regression at surgery (Mandard 1-3) occurred in 24/33 pts. Median recurrence free survival was 25.4 months (mo) (D-CapOx), 32.0 mo (D-FLOT) and not reached (D-CXRT). 2 year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. Conclusions: Adding D to standard neo-adjuvant regimens for GEC is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2 year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. Clinical trial information: NCT02735239 .
Safety and short-term efficacy of neoadjuvant FLOT therapy in patients with resectable esophageal squamous cell carcinoma.
Authors: Yuri Yoshinami, Shun Yamamoto, Toru Kadono, Toshiharu Hirose, Go Ikeda, Akihiro Ohara, Mai Itoyama, Kazuki Yokoyama, Yoshitaka Honma, Koshiro Ishiyama, Junya Oguma, Hiroyuki Daiko, Ken Kato
Journal: Journal of Clinical Oncology (2023)

373 Background: Docetaxel and cisplatin, 5-FU (DCF) is a standard neoadjuvant treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 study. However, DCF therapy showed that 18.6% of patients achieved pathological complete response but 16.3% had febrile neutropenia (FN) and needed hydration. In Western countries, 5-FU plus leucovorin, oxaliplatin, docetaxel (FLOT) is a standard perioperative treatment for resectable gastric and esophagogastric junction adenocarcinoma patients. FLOT therapy showed that 2% of patients had FN and did not need hydration. However, safety and efficacy of neoadjuvant FLOT (NeoFLOT) in locally advanced ESCC patients was unclear. Methods: The subjects for this study were patients with resectable ESCC diagnosed as cT1N1-3M0, cT2-3N0-3M0, and cT1-3N0-3M1 (UICC-TNM 8th) and received NeoFLOT therapy between Feb 2021 to July 2022 at our hospital. NeoFLOT therapy (oxaliplatin: 85 mg/m2, leucovorin: 200 mg/m2, 5-FU: 2600 mg/m2, docetaxel: 50 mg/m2, every 2 weeks) was administered for 4 courses. We evaluated adverse events (CTCAE ver. 5.0) and histopathological response. Results: We identified 16 eligible patients and 12 of all patients (75%) underwent surgery. 4 patients (25%) resulted in progressive disease (1 patient underwent chemoradiotherapy and 3 patients underwent surgery). R0 resection rate was 75% and complete pathologic response in primary tumor was seen in 2 patients (17%). The most common adverse events were hematologic toxicity, with grade 3 or 4 leukopenia in 6 patients (38%), neutropenia in 9 patients (56%). The common non-hematological toxicity, with all grades deceased appetite in 7 patients (44%) and malaise in 8 patients (50%), peripheral neuropathy in (44%). Furthermore, the incidence of FN was 6%. In patients with grade 2 or higher renal failure, no one (0%) had worsened renal function. Conclusions: NeoFLOT therapy showed well-tolerated and comparable efficacy with DCF therapy.
Feasibility of circulating tumor DNA (ctDNA) to guide organ preservation in patients with node-negative rectal cancer undergoing neoadjuvant chemotherapy, excision, and observation in the phase II CCTG CO.28 trial.
Authors: Jonathan M. Loree, Russell Madison, Christopher J. O'Callaghan, Carl J Brown, Dongsheng Tu, Derek J. Jonker, Max Sherry, Alexander D. Fine, Yanmei Huang, William Camara, Prapti Pokharel, Alexey Aleshin, Geoffrey R. Oxnard, Hagen Fritz Kennecke
Journal: Journal of Clinical Oncology (2023)

180 Background: CCTG CO.28 evaluated 3 months of neoadjuvant CAPOX or FOLFOX followed by transanal excision surgery (TES) in patients (pts) with T1-T3, N0 rectal cancers with the goal of organ preservation. Total mesorectal excision (TME) was recommended for inadequate downstaging or high-risk features on TES pathology. Detection of ctDNA is associated with a high rate of recurrence in high risk resected colorectal cancer. However, the sensitivity of ctDNA in early-stage rectal cancer is unclear. Methods: Tissue CGP was performed retrospectively on pretreatment resected tumor using Foundation OneCDx (F1CDx), followed by MRD detection using FoundationOneTracker. Briefly, variants were selected from F1CDx using an algorithm that filters out non-tumor derived variants (e.g. germline). A tumor-informed personalized multiplex PCR-next generation sequencing assay, consisting of up to 16 variants, was used to detect ctDNA and quantify plasma mean variant allelic frequency (VAF) and mean tumor molecules per mL of plasma (MTM/mL). FoundationOneTracker was performed on blood samples collected pre/post-neoadjuvant chemotherapy. Buffy coat sequencing was performed at FMI to validate the monitoring variant selection algorithm. Results: 52 pts underwent F1CDx and FoundationOneTracker analysis. KRAS mutations were observed in 60% (n =31) of cases; MSI-H and BRAF V600E mutations were not detected. From 1,580 distinct variants detected in tissue and paired buffy coat sequencing, 985 had VAF &gt;30% in the buffy coat specimen and were considered germline. The variant selection algorithm filtered 99.8% (n = 983) of germline variants; the remaining 2 were not selected for primer design. A median of 7 variants (range 2-16) were tracked per pt. Detectable ctDNA was found in 0% (0/6), 19% (6/32) and 55% (6/11) of treatment naïve T1, T2 and T3ab cases, respectively, and 83% of those which were initially positive (10/12) cleared ctDNA post chemotherapy. Three pts had detectable ctDNA pre-excision, including 1 who was negative pretreatment. From 42 pts with pre/post-treatment plasma, 19 pts were recommended for TME; 2 had detectable ctDNA, 5 had ctDNA clearance, and 12 had no ctDNA detection. Conclusions: Node-negative rectal cancer exhibited ctDNA shed in a minority of pts, with most clearing ctDNA on chemotherapy before their TES. The dynamic ctDNA signal we demonstrate could supplement clinical factors in informing organ preservation in very early-stage rectal cancer. Larger studies are needed to determine if this information can be used to personalize therapy. Clinical trial information: NCT03259035 . [Table: see text]
Toxicities and outcomes of neoadjuvant treatment in elderly patients with locally advanced rectal cancer: A scoping review.
Authors: Ruba Ahmed Mohammed Hamed, Greg Korpanty, Dervla Kella
Journal: Journal of Clinical Oncology (2023)

91 Background: Neoadjuvant treatment (NAT) followed by surgery has become the standard treatment for locally advanced rectal cancer (LARC). This scoping review aims to assess the toxicity and outcomes of the currently available NAT of rectal cancer in elderly patients with age-associated frailty. Methods: Six thousand seventy-nine records were identified on Ovid Medline, Embase, Cochrane database, and CINAHL. Two independent reviewers screened the articles. Fifteen articles were identified through a hand search. Articles on NAT in LARC in elderly patients were included. Results: Thirty-three studies from 2005 to 2022 met inclusion criteria, including 27 retrospective reviews, 4 clinical trials (Phase 1 and 2) and 2 prospective studies; 5 were multicentred. The median age of the sample was 70-75 in 24 studies and 76-83 in 11 studies. One study examined only patients above 80. Twenty-four studies examined NAT with long course concurrent chemoradiotherapy (LCCRT), 5 examined both LCCRT and RT alone, 3 examined short-course radiotherapy (SCRT), one examined SCRT with sequential chemotherapy (CT), and one study examined neoadjuvant CT followed by LCCRT. Concurrent CT with 5 FU-based treatments was given in 23 studies with either intravenous or oral, and oxaliplatin was added to 5 FU in 10 studies. Interruption of concurrent treatment was reported with dose reduction, delay or discontinuation in 26 studies. Diarrhea, nausea/vomiting and radiation dermatitis were reported as significant side effects (G3 -4), with G3-4 diarrhea reported in 18 studies. Haematological toxicities were very frequent, with a 20-60% rate in the studies. No dose interruption of RT was required in the three studies that included only SCRT, except for one patient. The study on CT followed by LCCRT showed that CT was completed in 82% and LCCRT in 76% of patients. A preliminary result of PRODIGE 42-GERICO 12 NACRE, a randomised trial comparing SCRT with chemoradiotherapy (CRT), showed that 14% of patients in the CRT arm did not receive all of the planned treatment compared to 0% in SCRT arm, and the 6 months death rate was 10.0% in CRT arm and 3.92% in SCRT. Conclusions: Toxicities are frequently reported with Neoadjuvant LCCRT in the elderly and lead to treatment interruption. SCRT is well tolerated and probably associated with better survival (pending final results of the NACRE trial). Studies in this scoping review are over-represented by retrospective studies, and we suggest that future clinical trials focus on elderly patients to investigate treatment strategies with fewer toxicities.